Background: Primary progressive aphasia (PPA) is a clinical dementia syndrome characterized by impairments in language. The presence of Alzheimer disease (AD) neuropathology has been observed in approximately 40% of PPA cases. Cross-sectional and longitudinal features of cortical atrophy in PPA are emerging but less is known about the integrity of subcortical structures, particularly the thalamus. As a major relay station in the brain, the thalamus is implicated in language functioning given its reciprocal connections with perisylvian regions in the cortex. High-dimensional brain mapping was used to characterize thalamic morphology in individuals with and without non-semantic PPA. Further, shape differences were compared between PPA participants with suspected AD pathology (PPAAβ +) and those without suspected AD pathology (PPAAβ -) as determined by amyloid PET scans. The relationship between shape and specific language deficits were also investigated. Method: Thalamic integrity was examined in 57 PPA participants relative to cognitively healthy controls (N=44) with similar demographics. MR scans were acquired using high-resolution T1-weighted MPRAGE volumes following the ADNI protocol. Thalamic shape features were estimated using Large Deformation Diffeomorphic Metric Mapping. Thalamic nuclei of interest included mediodorsal, pulvinar, and anterior regions. General linear models compared differences in thalamic shape between groups. Pearson models characterized relationships between thalamic nuclei and language function. Results: After controlling for whole brain volume, thalamic volume did not differ between groups [F(1, 99)=0.80, p=0.80]. However, PPA participants exhibited significant bilateral inward shape deformation in dorsal and ventral regions that extended in an anterior to posterior fashion, and unilateral outward deformation in medial and lateral regions only in the left thalamus relative to controls [F(9, 91)=5.75, p<0.001, Wilk's Λ=0.64]. There were no shape differences between PPAAβ + and PPAAβ – groups. Pearson models revealed significant correlations between confrontation naming and shape deformation in the left pulvinar (r=0.59, p<0.01) and left anterior (r=0.55, p<0.01) thalamic nuclei for the PPAAβ + group only, such that lower language scores reflected greater localized volume loss. Conclusions: In the absence of volumetric differences, shape measures were able to capture unique aspects of localized morphologic differences in PPA that corresponded to worse naming performance only in those with suspected AD pathology. Thalamic changes appear to be a contributing and unrecognized component to the presentation and language characterization of PPA.

Accumulation of amyloid beta (Aβ) in the brain is a pathological hallmark of Alzheimer's disease (AD) and has been shown to lead to synaptic dysfunction and cognitive decline. Recent studies have indicated synapse dysfunction as an early pathology in AD, but how synaptic function is altered by Aβ remains unclear. We hypothesize that neuronal functional stability may be altered by Aβ via dysregulation of homeostatic synaptic plasticity (HSP), a negative-feedback-based regulation that serves to restrain neuronal activity within a physiological range. Here, I show that Aβ can regulate HSP in response to activity deprivation with an over scaling up of postsynaptic AMPAR expression and excitatory synaptic currents. Aβ treatment during activity deprivation increases the surface expression of both calcium-permeable (Cp), GluA2-lacking (CpAMPARs) and regular, GluA2-containing AMPARs. This in turn may make neurons more vulnerable to neuronal injury after a toxic glutamatergic challenge. Homeostatic synaptic scaling requires the PI3K/Akt signaling pathway and expression of CpAMPARs. Consistent with this, I found that blockade of either PI3K or CpAMPARs occludes over-scaling in the presence of Aβ, suggesting that the enhancement of HSP is mediated through homeostatic mechanisms. Furthermore, challenging neurons with glutamate after Aβ-mediated enhancement of HSP shows increased neuronal death. These findings provide a novel mechanism by which Aβ alters neuronal plasticity and calcium homeostasis in the brain, suggesting that the HSP pathway may be a target in clinical treatment of Alzheimer's disease.

Dysfunction in the Sigma-1 receptor (Sig-1R) is implicated in many neurodegenerative diseases such as Alzheimer’s Disease (AD). Recently, agonists of the Sig-1R have been found to be neuroprotective in AD and provide significant improvements in symptoms. The hallmarks of AD are aggregation of amyloid-β (Aβ) plaques and development of neurofibrillary tau tangles in the brain, which are thought to be correlated with progressive neuronal cell death in AD. Aβ leads to increased endoplasmic reticulum (ER) stress, decreased autophagy, and increased apoptosis, all of which may be contributing to the neuronal cell death that is seen in AD. The Sig-1R is known to reduce ER stress, increase autophagy, and decrease apoptosis. However, as of yet there is little research on the ability of the Sig-1R to specifically reduce Aβ toxicity through these pathways. Therefore, through the use of in vitro and ex vivo models, this study examined the pathways through which activation of the Sig-1R may exert its protective effects against Aβ toxicity. Here, it is shown that activation of the Sig-1R reduces neuronal cell apoptosis in vitro, and reduces tissue death in the CA3 region of the hippocampus ex vivo. Furthermore, this reduction in cell and tissue death may be a result of reduction of ER stress and a return towards baseline levels of autophagy. Together, this research provides insight as to how the Sig-1R may be an important therapeutic target in AD through protection against apoptosis and tissue death.

Alzheimer’s disease is characterized by the formation of two major pathological hallmarks: amyloid plaques and neurofibrillary tangles. Although there have been many studies to understand the role of microglia in Alzheimer’s disease, it is not yet known how microglia can promote disease progression while actively phagocytosing amyloid plaques or phosphorylated tau (p-tau). Through stereotaxic injection of adeno-associated virus expressing mutant P301L tau (AAV-P301L-tau) into the medial entorhinal cortex (MEC) of both wild-type (WT) and APPNL-G-F mice, we demonstrate how amyloid plaques exacerbate p-tau propagation to the granule cell layer (GCL) of the hippocampus. However, in mice receiving the colony-stimulating factor 1 receptor inhibitor (PLX5622), ~95% of microglia were depleted, which dramatically reduced p-tau propagation to the GCL. Although microglia depletion curtailed p-tau propagation, it also led to reduced plaque compaction and an increase in overall amyloid-beta (Aβ) plaque presence. Additionally, we found microglia depletion resulted in greater p-tau aggregation in dystrophic neurites surrounding amyloid plaques. We investigated neurodegenerative microglia (MGnD), which are activated in response to amyloid plaques, for their propensity to release extracellular vesicles in comparison to homeostatic microglia. We discovered that MGnD, identified by Clec7a or Mac2 staining, strongly express Tumor susceptibility gene 101 (Tsg101), which is an ESCRT-1 protein and a marker for extracellular vesicles (EVs). To further investigate EV release and MGnD, a novel lentivirus expressing fluorescent mEmerald conjugated to CD9 (mE-CD9) was constructed and injected into the MEC of both WT and APPNL-G-F mice which allowed for visualization of mE-CD9+ puncta around individual microglia. CD9 is a tetraspanin and also a marker for EVs. We observed that the number of mEmerald+ particles surrounding MGnD was three-fold higher compared to non-diseased, homeostatic microglia. Sequential injection of mE-CD9 and AAV-P301L-tau into the MEC revealed that microglia-derived EVs encapsulate pathologic p-tau, which is augmented by the MGnD phenotype. Taken together, these data provide strong evidence that MGnD exhibit increased secretion of tau-containing EVs, providing a possible mechanism for how amyloid deposition indirectly exacerbates tau propagation.

No description available.

Indiana University-Purdue University Indianapolis (IUPUI) / Alzheimer’s disease (AD) is a neurodegenerative disease histopathologically characterized by the coexistence of amyloid plaques and neurofibrillary tangles, mainly consisting of amyloid β peptides hyperphosphorylated tau proteins, respectively. Multiple proteins and pathways are involved in the pathogenesis of AD, including Aβ precursor protein (APP), β-site APP-cleaving enzyme (BACE1), neprilysin, endothelin converting enzyme (ECE), repressor element-1 silencing transcription factor (REST), microtubule-associated protein tau, glycogen synthase kinase, and pro-inflammatory cytokines. However, how these proteins and pathways are dysregulated and converge in AD pathogenesis remains unclear. Genetic, epigenetic and environmental factors play important roles in disease progression. MicroRNAs (miRNAs), a group of small noncoding RNAs, are important epigenetic regulators that participate in AD development. We have identified three miRNAs capable of targeting several proteins in different AD-related pathways: miR-181-5p, miR-153-3p and miR-101-3p. We tested miR-181 activity with recombinant reporter gene- MME 3’-UTR constructs. All four miR-181-5p (miR-181a, miR-181b, miR-181c and miR-181d) sequences downregulated the reporter signal. Human differentiated neural cells were transfected with miR-181d-5p mimics. miR-181d-5p treatment significantly reduced MME mRNA levels, protein levels and enzyme activity. In addition, miR-181d-5p increased tau and phosphorylated tau levels proportionally. We further demonstrate that miR-153-3p reduced REST 3’-UTR activities, mRNA and protein levels in multiple human cell lines. Moreover, we show that miR-153-3p, by knocking down REST protein, induces apoptosis in HeLa cells but not differentiated neural cells. In addition, miR-153-3p regulates neuronal differentiation in neuronal stem cells, potentially via REST knockdown. We further found that miR-153 levels were correlated with a reduced likelihood of developing AD. Last, we demonstrated that miR-101-3p reduced ECE1 and GSK3β protein levels in multiple cell lines. miR-101-3p increased REST and pro-inflammatory cytokine secretion in microglia cells. In sum, we tested the hypothesis that miRNAs can serve as the master regulator of AD pathogenesis. / 2024-07-01

Alzheimer’s Disease (AD) is a chronic neurodegenerative disease commonly characterized by the aggregation and deposition of insoluble amyloid beta plaques throughout the brain, and by an associated neuroinflammatory response to these plaques involving astrocytes and microglia. Choline is an essential nutrient with diverse functional roles that has emerged as a promising candidate for the treatment of AD. Localized plaque regions in the polymorphic layer in the medial dentate gyrus of the hippocampus and in the cortex were examined in 9-month-old APP-NL-G-F knock-in AD model mice to determine the effects of perinatal choline supplementation on astrocytosis and gliosis associated with amyloid beta. The size of ionized calcium-binding adaptor molecule 1 (Iba1)-positive cells and clusters were larger in control diet APPNL-G-F mice, although the number and total area covered by Iba1+ cells/clusters were decreased compared to those of control diet C57BL6/J mice. In comparison, choline supplementation significantly reduced the size of Iba1+ cells/clusters in APPNL-G-F mice. These results suggest that perinatal choline supplementation ameliorates neuroinflammatory processes associated with amyloid plaques in these 9-month-old APPNL-G-F mice, and that dietary supplementation of choline might serve as an effective treatment for AD. / 2026-02-14T00:00:00Z

One of the most prevalent diseases acquired in older populations and currently the most common form of dementia, exists in the form of Alzheimer's [1]. Progressing over time, Alzheimer's begins intramolecularly through the buildup of amyloid precursor protein derived Aβ peptides which aggregate into neurotoxic fibrils. The fibrils result in damage to memory and cognitive systems, leading to depression of routine function and eventual death. There is currently no cure nor treatment by which this plaque buildup can be prevented or eliminated, and as such, significant work is being made towards this topic. It has been recently discovered that the human matriptase protein is capable of cleaving both the amyloid precursor protein from which Aβ peptides are made as well as the Aβ1-42 peptide itself, facilitating interest into its potential to reduce fibril formation [2][3]. In this study we set out to determine if the human matriptase serine protease domain can cleave Aβ fibrils or prevent the Aβ fibril formation in vitro. A recombinant matriptase serine protease domain (r-MatPD) was subcloned into a pET-28a-c(+) expressing vector, expressed, and purified via Ni-NTA affinity resin. The purified his-tagged r-MatPD was further auto-activated and incubated with the purified recombinant Aβ1-42 peptides. We observed that r-MatPD can cut polymerized Aβ1-42 into smaller fragments and prevent Aβ1-42 fibril formation. Effectively, this study suggested that the matriptase protease domain can be further investigated for its role in Aβ fibril clearance in vivo with a possibility of developing matriptase therapeutic potentials in treating Alzheimer's patients.

No description available.

No description available.